Tuberculosis is the leading cause of death due to an infectious disease despite effective medications to treat and prevent this infection. The only available TB vaccine, BCG, has variable effectiveness but is most effective against miliary and meningeal TB, two severe forms of extrapulmonary TB. BCG also appears to be more effective in young children than it is in adults. Interestingly, extrapulmonary TB in general, and miliary and meningeal TB in particular, are more common in young children than in adults. The factors which predispose HIV-seronegative children and adults to extrapulmonary TB are unknown, as are the factors which underlie the age-related differences in the clinical manifestations of TB. Interferon-gamma is critical in the host immune response to mycobacterial infections. Defects in interferon-gamma production and genetic abnormalities that result in defects in the interferon-gamma receptor, have been identified in HIV- seronegative children with disseminated nontuberculosis mycobacterial infections. Interferon-gamma is also critical in the host immune response to M. tuberculosis infection. We hypothesize that abnormalities in the interferon-gamma cytokine response pathway contribute to the development of extrapulmonary or disseminated TB. We propose to investigate the risk factors for extrapulmonary TB through four case-control studies. First, we will compare cytokine responses to mitogen stimulation in HIV- seronegative adults with extrapulmonary TB compared to the cytokine response in PPD+ adults without active TB. Second, we will compare cytokine responses in children less than 5 years old with miliary/meningeal TB to PPD+ children less than 5 years old without active TB. The third aim of this proposal is to assess for the prevalence of genetic abnormalities specific to the interferon-gamma cytokine response pathway among persons with extrapulmonary TB and controls in the same two populations. New insights into the predisposition to disseminated or extrapulmonary TB will increase our understanding of the pathogenesis of M. tubercuolosis infection, and help identify persons at risk for these severe forms of TB. These investigations will also help identify persons who would benefit most from TB vaccination. The insights gained may also lead to an improved understanding of the mechanisms through which BCG protects against TB, and identify ways in which to develop a more effective TB vaccine.